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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS 

PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: PV Shah, 703-308-1846

Jeneil Biosurfactant Company

[IN-10853]

EPA has received a pesticide petition (IN-10853) from Jeneil Biosurfactant Company, 400 

N. Dekora Woods Blvd. Saukville, WI 53080 proposing, pursuant to section 408(d) of the Federal 

Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.

to establish an exemption from the requirement of a tolerance for

Phenyl ethyl acetate (CAS Reg. No. 103-45-7) when used as an inert solvent applied to 

growing crops or harvested crops under 40 CFR 180.910 in pesticide formulations. EPA has 

determined that the petition contains data or information regarding the elements set forth in 

section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the 

submitted data at this time or whether the data supports granting of the petition. Additional 

data may be needed before EPA rules on the petition.

A. Residue Chemistry NA remove

1. Plant metabolism.

2. Analytical method. NA remove

3. Magnitude of residues. NA remove

B. Toxicological Profile Phenylethyl acetate, a natural component of a variety of foods, 

metabolizes readily to innocuous products, as described in Section 7. Therefore, oral toxicity 

resulting from the use of phenylethyl acetate as an inert ingredient in pesticides is not expected 

to be significant. To further evaluate the toxicity of phenylethyl acetate, several data sources 

were utilized: the safety evaluations for reaffirmation of GRAS status performed by the Expert 
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Panel of the Flavor and Extract Manufacturers Association (FEMA); the Joint FAO/WHO Expert 

Committee on Food Additives’ (JECFA’s) Food Additive Series on phenylethyl alcohol, aldehyde, 

acid and esters and related substances; the Research Institute on Fragrance Materials (RIFM’s) 

toxicological and dermatological assessment of aryl alkyl alcohol simple acid ester derivatives; 

and U.S. EPA’s HPV Challenge Program dossier on phenylethyl alcohol submitted by the Flavor 

and Fragrance High Production Volume Chemical Consortia/ Aromatic Consortium (FFHPVCC). 

Toxicity data on phenylethyl alcohol and phenyl acetic acid are also considered relevant in this 

analysis because the metabolism of phenylethyl acetate proceeds rapidly to generate these two 

compounds. In addition, toxicity of other phenethyl esters and phenoxyethyl alcohol or 

phenoxyacetic acid is thought to be relevant to that of phenylethyl acetate because 1) they all 

have a 2-phenethyl or 2-phenoxyethyl carbon skeleton containing a primary oxygenated 

functional group; 2) they all have similar pharmacokinetic properties and go through nearly 

identical metabolic pathways, as described above, ultimately leading to the production and 

excretion of phenylacetic acid or phenoxyacetic acid; and 3) all of these compounds are natural 

dietary components.

1. Acute toxicity. Acute toxicity tests categorize phenylethyl acetate into acute toxicity 

category III or IV for oral exposure and category IV for dermal and inhalation exposure. Oral LD50

values for phenylethyl acetate in rats range from 3700 mg/kg bw to 5200 mg/kg bw. The dermal 

LD50 in rabbits was 6210 mg/kg bw in one study and reported as <10,000 mg/kg bw in another. 

The inhalation LC50 in rats was >500 mg/m3.

2. Genotoxicty. The Research Institute for Fragrance Materials, Inc. (2012) reported 

results of three Ames assays performed on phenylethyl acetate, two of which were OECD 

guideline 471 studies. Results of all three showed no significant increase in reverse mutations in 

Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of 

metabolic activation at concentrations up to 5000 μg/plate phenylethyl acetate. The 

genotoxicity of phenylethyl alcohol and six of its derivatives to in vitro and bacterial systems is 

presented in the following table.

Table 4 – In Vitro Genotoxicity of Phenylethyl alcohol and its Derivatives (from JECFA 2003)

Compound Endpoint Organism/cell type Maximum 

concentration Result 

Phenylethyl alcohol Reverse 

mutation

S. typhimurium TA98, 

TA100, TA1535, 

TA1537

3 mmol/plate Negative
3

Sister chromatid 

exchange Human lymphocytes Not specified Negative

Phenylacetaldehyde

Reverse 

mutation

S. typhimurium TA98, 

TA100, TA104 Not specified Negative

Mutation E. coli 

WP2uvrA/pkM101 Not specified Negative

Phenylacetic acid

Reverse 

mutation

S. typhimurium TA98, 

TA100, TA1535, 

TA1537, TA1538

1000 mg Negative

Unscheduled

DNA synthesis Rat hepatocytes 500 mg Negative

Mutation Mouse lymphoma 

L5178Y Tk+/– cells 1500 mg Negative

Ethyl phenylacetate

Mutation B. subtilis H17 (rec + ) & 

M45 (rec –)

21 mg/disc Negative

Mutation B. subtilis H17 (rec + ) 

and M45 (rec –)

20 ml/disc Positive

Reverse 

mutation

S. typhimurium TA92, 

TA94, TA98, TA100, 

TA1535, TA1537

5 mg Negative

Chromosomal 

aberration

Chinese hamster 

fibroblast cells 1 mg/ml Negative
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Mutation E. coli WP2uvrA (trp–)

200–1600

μg/plate Negative

Isobutyl 

phenylacetate

Reverse 

mutation

S. typhimurium TA97, 

TA102 0–0.1 mg/plate Negative

Isoamyl 

phenylacetate

Mutation B. subtilis H17 (rec + ) 

and M45 (rec –)

20 mg/disc Positive

Mutation B. subtilis H17 (rec + ) 

and M45 (rec –)

20 ml/disc Negative

Reverse 

mutation

S. typhimurium TA98, 

TA100

10 mg/plate Negative

50 mg/plate Lethal

paraTolylacetaldehyde

Reverse 

mutation S. typhimurium TA100 0.1–1000μg/plate Negative

Mutation E. coli PQ37 Not specified Negative

In vivo assays of genotoxicity were negative in three chemicals structurally related to 

phenylethyl acetate. First, ester isoeugenol phenylacetate did not significantly increase the 

number of micronucleated polychromatic erythrocytes in NMRI mice following intraperitoneal 

(ip) injections of 1100-2800 mg/kg bw. This compound also did not increase the frequency of 

sex-linked lethal mutations in Drosophila melanogaster receiving 25 mmol/L for three days. 

Similarly, there was no significant and biologically-relevant increase in micronucleated 

polychromatic erythrocytes in mice following ip injections of 625–1875 mg 2-phenoxyethyl 

isobutyrate/kg bw or gavage doses of 500–2000 mg/kg bw sodium 2-(4-

methoxyphenoxy)propanoate.

3. Reproductive and developmental toxicity. Although there were no developmental 

toxicity data on phenylethyl acetate, there were several studies identified for phenylethyl 

alcohol and phenylacetic acid, the two principal metabolic products of phenylethyl acetate. Old 

developmental toxicity screening studies of gavage-administered phenyl ethyl alcohol found 
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teratogenic effects resembling Fetal Alcohol Syndrome. When subsequent developmental and 

reproductive studies failed to reproduce these findings using dermal or dietary administration 

routes, a study of the pharmacokinetics of phenyl ethyl alcohol was undertaken. 

Pharmacokinetic studies of phenylethyl alcohol showed that peak plasma levels of the 

metabolite phenylacetic acid, which was determined to be the chemical associated with 

observed toxicity, were significantly higher when administered by gavage compared to other 

routes. Dermal application garnered less than one-tenth that of gavage with respect to area 

under the curve and peak plasma concentration. The lowest in vivo concentrations were seen 

after dietary administration. Therefore, the results of the dietary and dermal studies presented 

here are thought to more accurately represent a realistic exposure scenario for phenylethyl 

alcohol or acetate compared to the gavage results.

Phenyl ethyl alcohol was fed in a microencapsulated form to Sprague-Dawley rats during GD 6–

15 at doses of 0, 50,150 or 500 mg/kg bw/day. The actual intake was calculated to be 83, 266, 

and 799 mg/kg bw/day for the three dose groups. Animals were sacrificed on GD20 and litter 

values were assessed and fetuses evaluated for structural malformations or anomalies. The 

effect on dams at the high dose was decreased food consumption, resulting in slight weight loss 

during the first 2 days of treatment. Malformation incidence was not dose-dependent and did 

not differ significantly in quantity or type between dose groups and control. An increased 

incidence of incomplete calcification was seen in fetuses of high dose and this was considered to 

be a possible consequence of the impairment of maternal weight gain. No other evidence of 

embryotoxicity or developmental toxicity was reported. The NOELs from this study for both 

maternal and developmental effects were 266 mg/kg/day, and the LOELs were 799 mg/kg/day. 

Sprague-Dawley rats received topical doses of 140, 440 or 1400 mg/kg bw/day phenyl ethyl 

alcohol on GDs 6-15. Dams receiving 1400 mg/kg bw/day exhibited clear signs of systemic 

toxicity including death or sacrifice of 3/35 rats, irritability, hunched posture, walking on toes, 

piloerection, a brown “deposit” in the area of contact, and suppression of mean food intake and 

growth rate. Animals recovered after cessation of dosing. One non-pregnant female rat at the 

middle dose displayed similar clinical signs of toxicity as high dose rats, but no other adverse 

effects were noted in pregnant or non-pregnant females at this dose. The NOAEL for maternal 

effects was determined to be 440 mg/kg/day.

At the high dose there was an increase in resorptions, a decrease in mean litter size and fetal 

weight, a wide range of soft tissue and skeletal changes, and incomplete ossification. At the 

middle and low doses, there were clear dose-related increases in certain visceral abnormalities 

that were: 1) not seen in controls, 2) not historically common in that strain of rat, and 3) also 

increased significantly in the high dose group. The pattern of responses suggested a relationship 

with dose, but was not strictly linear. In the skeletal exam, there was clear evidence of a dosagerelated trend in the increased incidence of litters and fetuses with cervical rib(s) and defects of 

thoracic vertebrae beginning at the lowest dose. The incidences of moderate, commonly 

observed abnormalities in ossification were clearly dose-related, though not significant at the 

low dose. Litter parameters were not affected. Authors concluded that overall, there was 
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conclusive evidence of an effect on development at the high dose and clear evidence of an 

effect at the mid-dose. The slight differences from control values observed at the lowest dose 

were not statistically significant. The NOAEL for developmental effects of phenyl ethyl alcohol by 

the dermal exposure route is140 mg/kg bw/day and the LOAEL is 440 mg/kg/day.

A follow-up dermal study looked specifically at cervical rib bud and thoracic vertebrae effects of 

phenyl ethyl alcohol. Pregnant rats were treated topically with 70, 140, 280, 430 or 700 mg/kg 

bw/day on GD 6-16. The incidence of cervical rib buds at the highest dose was statistically 

significantly higher than controls; there were no significant vertebrae effects. In all dose groups, 

there was significant, dose-related skin irritation in dams. The LOAEL for maternal effects was 70 

mg/kg bw/day, the lowest dose. At all doses, fetuses showed seemingly reversible delayed 

ossification, which was not dose-related in the two lower dose-groups. Conservatively, the 

NOAEL for developmental effects in this study was 140 mg/kg/day, however effects seen at this 

dose may have been associated with maternal irritation and therefore a true developmental 

NOAEL cannot be derived from these data. 

In summary, developmental effects were not observed in rats after oral administration of 

phenylethyl alcohol in the absence of maternally toxic doses. Dermal exposure, on the other 

hand, produced developmental toxicity at 440 mg/kg/day. This difference in toxicity based on 

route of exposure is consistent with previous pharmacokinetic data on phenyl ethyl alcohol in 

which dermal penetration and peak plasma concentrations in rats were shown to be higher 

compared with dietary administration.

Repeat oral doses of phenethyl phenylacetate or phenyl ethyl alcohol, did not cause an adverse 

response in reproductive organs, even in animals receiving the highest dose levels (500 

mg/kg/day phenethyl phenylacetate and 120 mg/kg/day phenyl ethyl alcohol). A dermal repeatdose study indicated that a dose of 2000 mg/kg bw/day phenyl ethyl alcohol resulted in an 

increase in relative gonad weight in male rats. These results suggest that these related 

chemicals are not reproductive toxins, except at very high doses. 

Female Sprague-Dawley rats (10/group) received gavage doses of phenylacetic acid at 250, 500, 

and 1000 mg/kg bw/day gavage in either a 1% methylcellulose or corn oil vehicle. Dosing lasted 

from one week prior to a cohabitation period through gestation, parturition, and a 4-day 

postpartum period, for a total dosing duration of 39 days. Phenylacetic acid at the lowest dose 

(250 mg/kg/day) produced significant clinical signs of toxicity in dams (excess salivation, ataxia, 

urine staining), reduced body weight and body weight gain throughout premating, gestation, 

and lactation, and reduced feed consumption. These effects were reported at higher doses too, 

along with increased mortality. The NOAEL for systemic toxicity in dams was less than 250 

mg/kg bw/day. Fertility parameters and gestation length in treated dams were not statistically 

different from those of control rats. Offspring of dams in the high dose group showed decreased 

viability during postpartum days 1-4 and decreased body weights postpartum compared with 

control animals. However, because dams at this high dose were clearly affected by the test 

substance, it is not possible to differentiate this effect on reproduction from the maternal 
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effects. Furthermore, as previously stated, pharmacokinetic studies showed that peak plasma 

levels of phenylacetic acid were significantly higher when administered by gavage compared to 

other routes. Therefore results observed in the dams in this study are probably not 

representative of real world exposures. 

4. Subchronic toxicity. Like phenylethyl acetate, phenethyl phenylacetate will produce 

the metabolites phenylethyl alcohol and phenylacetic acid. Toxicity of these two compounds to 

mammalian systems, therefore, will be very similar. The oral toxicity of phenethyl phenylacetate 

was assessed by the U.S. Food and Drug Administration (FDA) in Osborne-Mendel rats 

(10/sex/dose). Animals received diets containing 0, 1,000, 2,500 or 10,000 ppm phenethyl 

phenylacetate, for an average daily intake of 0, 50, 250 or 500 mg/kg bw, for 17 weeks. At the 

end of that period, the liver, kidneys, spleen, heart, and testes were weighed and histological 

evaluation was carried out on these organs as well as the remaining abdominal and thoracic 

viscera, bone, bone marrow, and muscle. Detailed microscopic examinations were performed on 

a subset of the rats in the high dose and control groups. There was no effect of the test 

compound on body weight, food intake, hematological endpoints, or organ weights, and nothing 

observed in the gross examination of tissues, or histological examination at any dose. The 

NOAEL therefore was 500 mg/kg bw/day phenethyl phenylacetate, the highest dose.

A 90-day dermal toxicity study was carried out on Sprague-Dawley rats (15/sex/group) phenyl 

ethyl alcohol at daily doses of 0, 250, 500, 1,000 or 2,000 mg/kg bw. At the two highest dose 

groups test animals exhibited a statistically significant lower growth rate than controls. There 

was also a statistically significant decrease in hemoglobin and white blood cell count in males 

and increases in relative brain, kidney and gonad weights at the high dose only. No other 

significant effects were noted in the clinical examination or hematology and urine analysis. No 

findings were reported upon histopathological examination of any organ or tissue, including: 

adrenals, brain, heart, kidneys, liver, lung, mesenteric lymph node, pituitary, sternum, spinal 

cord, testes with epididymides, ovaries, spleen, urinary bladder and nerve. The study author 

reported a NOAEL of 500 mg/kg bw/day, corresponding to an internal dose of 350 mg/kg 

bw/day.

5. Chronic toxicity. The oral toxicity of phenylethyl alcohol was assessed in rats as one 

component in a mixture. Twenty Wistar albino rats per sex received a mixture of compounds 

dissolved in their drinking water for 56 weeks. The mixture comprised phenylethyl alcohol at 

120 mg/kg bw (0.12%), ethyl alcohol at 6000 mg/kg bw (6%), ethyl acetate at 4 mg/kg bw 

(0.004%), isoamyl alcohol at 120 mg/kg bw (0.12%), isobutyl alcohol at 200 mg/kg bw (0.2%) and 

acetic acid at 200 mg/kg bw (0.2%). A control group received tap water only. Body weights were 

monitored throughout and activities of alcohol dehydrogenase, alanine and aspartate 

aminotransferases, and protein content of liver were determined at 2–4-week intervals. There 

were no differences between control and treatment groups with respect to weight, hematology, 

or histology of liver, kidneys, heart, spleen and lungs. Hence, there was no significant effect of 

chronic exposure to 120 mg/kg/day of phenylethyl alcohol on rats.
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6. Animal metabolism. Studies of the metabolism of aromatic esters, including 

phenylethyl acetate, in simulated gastric and pancreatic juices indicate hydrolysis is rapid and 

precedes absorption. The hydrolysis products are absorbed very quickly after entering the 

gastrointestinal system. 

Phenylethyl acetate forms phenylethyl alcohol and acetic acid via reactions of the 

carboxylesterases or esterases, which predominate in hepatocytes but are present in most 

tissues throughout the body, including small intestine, colon, kidney, trachea and lungs. Acetic 

acid will be conjugated and excreted via urine or will undergo β-oxidation in the fatty acid 

metabolic pathway. Phenylethyl alcohol is oxidized via alcohol dehydrogenase to 

phenylacetaldehyde and then to phenylacetic acid via aldehyde dehydrogenases (ALDH). The Km 

and Vmax values of human mitochondrial and cytosolic ALDH isoenzymes, as well as the 

ubiquity of these enzymes, indicate rapid conversion to phenylacetic acid. Phenylacetic acid is 

an endogenous component of human urine formed during the breakdown of phenylalanine by 

intestinal bacteria or by oxidative deamination of endogenous phenethylamine. Conjugation of 

phenylacetic acid is dose-dependent and species-specific. The major conjugates are glucuronic 

acid, glycine, taurine or glutamine; some is eliminated as the free acid. Results of studies using 

radio labeled phenylacetic acid concluded that this compound is rapidly absorbed and

quantitatively excreted within 24 hours.

7. Metabolite toxicology. NA Remove

8. Endocrine disruption. Toxicity data related to endocrine disruption were not identified 

in the phenylethyl acetate database. As the scientific knowledge develops, screening of 

additional compounds may be added to the Endocrine Disruptor Screening Program (EDSP). 

When additional screening and/or testing is conducted, phenylethyl acetate may be the focus of 

screening and/or testing to better characterize effects related to endocrine disruption.

C. Aggregate Exposure

1. Dietary exposure. The estimated dietary exposure to phenylethyl acetate was 

determined using methods to estimate chronic dietary exposure for a generic inert ingredient. 

This assessment considers drinking water and crop-specific residues from pre-harvest 

applications of agricultural insecticides, herbicides and fungicides, assuming the highest 

established tolerance level residue for each commodity. The assessment assumes that the inert 

ingredient is used on all crops, and that 100% of all crops are treated with the inert. The inert 

ingredient is assumed to be present in all commodities treated with 57 of the most significant 

active ingredients at the maximum tolerance level as identified by the U.S. EPA for the default 

assessment. Chronic dietary exposure estimates were derived for the general US population 

and sub-groups of the population using the Dietary Exposure Evaluation Model, DEEMTM. The 

estimated chronic exposure for the total US population is 0.189 mg/kg/day, 3.79% of the chronic 

Population Adjusted Dose (cPAD). Children age 1 to 2 years old have the highest estimated 

exposure at 0.706 mg/kg/day, or 14.13% of the cPAD.
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i. Food. Dietary exposures of concern are not anticipated for phenylethyl acetate due to 

its ready biodegradation in the environment and low general toxicity. Residues will be minimal 

and, particularly in relation to background dietary consumption, not an important dietary 

source.

ii. Drinking water. Phenylethyl acetate exposure via drinking water from use as an inert 

ingredient is not expected to be significant. The phenylethyl acetate that enters the water will 

readily biodegrade. Exposure via the drinking water was estimated in the DEEM dietary 

exposure assessment assuming a concentration of 100 ppb.

2. Non-dietary exposure. Residential exposures of concern are not anticipated for 

phenylethyl acetate due to its ready biodegradation in the environment and low general 

toxicity. 

D. Cumulative Effects

Section 408(b)(2)(D) (9v) of the FFDCA requires that, when considering whether to 

establish, modify, or revoke a tolerance, the Agency consider “available information” concerning 

the cumulative effects of a particular pesticide’s residues and “other substances that have a 

common mechanism of toxicity.” To our knowledge there are no available data or other reliable 

information that suggests toxic effects produced by phenylethyl acetate would be cumulative 

with those of any other chemical compounds. EPA has not made a common mechanism of 

toxicity finding as to phenylethyl acetate and other compounds. Phenylethyl acetate does not 

produce toxic metabolites in common with other substances of potential concern. For the 

purpose of the tolerance exemption proposed, it is assumed that phenylethyl acetate does not 

share a common mechanism of toxicity with other substances. 

E. Safety Determination

1. U.S. population. There is a reasonable certainty that no harm to humans will result 

from the use of phenylethyl acetate as an inert ingredient in pesticide products. The oral 

Reference Dose (RfD) and chronic Population Adjusted Dose (cPAD) were derived based on the 

NOAEL of 500 mg/kg/day from the FDA 17-week dietary study of phenylethyl phenylacetate. For 

the total US population, the estimated chronic dietary exposure from food and drinking water 

for Phenylethyl acetate, calculated as 50% of all agricultural formulations, is 3.79% of the cPAD, 

well below any level of potential concern.

2. Infants and children. There is a reasonable certainty that no harm to infants and 

children will result from the use of phenylethyl acetate as an inert ingredient in pesticide 

products. Phenylethyl acetate is of low toxicity at doses expected from its inert use in pesticide 

formulations. The structurally similar and metabolically-related compounds phenethyl 

phenylacetate, phenylethyl alcohol and phenylacetic acid did not produce consistent evidence 

of developmental or reproductive toxicity following oral or dermal exposure for doses that were 

not also maternally toxic, nor was there evidence for endocrine disrupting properties. 
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Therefore, there is no concern for increased sensitivity to infants and children to phenylethyl 

acetate when used as an inert ingredient in pesticide formulations. For this reason, a safety 

factor analysis has not been implemented to assess risk and the additional tenfold safety factor 

for the protection of infants and children is also unnecessary. The estimated chronic dietary 

exposure from food and drinking water was highest (14.13% of cPAD) for children aged 1 to 2 

years old. This estimated exposure to phenylethyl acetate is well below any level of potential 

concern. 

F. International Tolerances

NA Remove